Melanoma is one of the most dangerous skin tumours with a steadily increasing incidence. Each year, 2 to 3 millions new skin cancers are diagnosed worldwide. Melanoma represents only 132 000 of these tumours but accounts for 79% of all cutaneous neoplasms deaths. Its global incidence has been increasing at a rate of around 3-8% per year in Europe since the mid 1960s. The main reason is the excessive exposure to sunlight and other sources of UV radiations, especially during childhood. Specifically, the current incidence of cutaneous melanoma is close to 10 000 new cases diagnosed per year in France. This is a highly invasive cancer, the development of which is rapidly fatal at the metastatic stage. 5-year survival does not exceed 14%, except in the case where the thickness of the tumour is less than 0.76 mm. In the case where the lesion exceeds this thickness, this tumour gives metastases in an unpredictable and silent fashion. This is why a search is currently underway for a method of investigation which makes possible the early evaluation both of the local extension and of the distant extension of the tumour. Moreover during the last decade, a number of radiopharmaceutical products, selected for their potential melanin affinity, have been experimented but few have had a satisfactory clinical development.
Early detection is crucial for prognosis. Significant progress have been made in the field of diagnosis, for instance with dermoscopy. Moreover, newly developed noninvasive functional imaging techniques such as positron emission tomography (PET) with the glucose analogue fluorine-18-labelled fluorodeoxyglucose ([18F]FDG) in association with fused anatomic CT images allows a significant increase in terms of spatial resolution and sensitivity of detection. In the case of melanoma, which can spread widely and unpredictably throughout the body, the use of [18F]FDG PET/CT whole-body imaging is very useful to localize all developing metastases in stage III or IV before surgery resection or in order to evaluate the regression of tumour volume during therapy. Nevertheless, this scintigraphic methodology can not discriminate between melanoma metastases and metastases of other origin. However, the use of nonspecific tracer [18F]FDG can be limited by the risk of false-positive findings due to an abnormal uptake by inflammatory areas for example. [18F]FDG PET scan is also very unlikely to identify metastases in brain or liver, which present a high physiologic background related to [18F]FDG metabolism. Moreover, this technique is inappropriate for the diagnosis of early-stage melanoma (stage I or II). In summary, the only method now valuable for staging primary melanoma remains the sentinel lymph node biopsy, which is much more sensitive. The diagnostic and clinical utility of [18F]FDG PET/CT imaging is best for patients with more advanced stages of disease.
Several biochemical targeting systems incorporating a lot of radionuclides for diagnosis have been also evaluated for early detection in SPECT or PET imaging of melanoma metastases, as example [123I]methylene blue dye, α-MSH analogues radiolabelled with fluorine-18, technetium-99 m, indium-111, yttrium-86 or copper-64, σ1 radioligands such as [18F]-1-(3-fluoropropyl)-4-(4-cyanophenoxymethyl)piperidine, analogues of thymidine or DOPA and various radiolabelled iodobenzamides.
If melanoma is diagnosed early (stage I or II), the most efficient treatment remains surgery. The malignant localized lesions, wherein the tumour thickness is <1.5 mm, can be cured by total resection. In this case, the success rates are approaching 90% survival at 5 years. Unfortunately, for tumours discovered when the skin lesion is already thick or ulcerated, so in case of an increased risk of metastatic disease (stage III or IV), the prognosis is very poor. In fact, the median survival rate is around 6 months and the success rates only reach 5% survival at 5 years, due to the lack of efficient therapies for metastatic malignant melanoma. For the postoperative adjuvant therapies, beneficial results were reported only for Interferon-α, which is the most commonly used to decrease the risk of recurrence. However, high doses usually administered cause substantial toxicity. The United States Food and Drug Administration have approved only two agents for the treatment of stage IV melanoma: dacarbazine and interleukin-2. Dacarbazine is an alkylating agent often used for chemotherapy. The overall response rate with this single therapy is around 22% and the median response duration is from 4 to 6 months. The oral analogue of dacarbazine, temozolomide, has also been developed. The response rate with this cytotoxic alkylating agent is comparable to this previously obtained. Interleukin-2 is a recombinant hormone of the immune system originally described as a T-cell-derivated growth factor. The response rate obtained with this therapy remains low (16%) and the treatment is often associated with significant toxic effects due to the high doses administered. None of these drugs has been shown to significantly prolong the survival of stage IV patients. Moreover, external beam radiotherapy can not be considered as an alternative because melanoma is described as radioresistant. Several clinical trials are under way in order to find novel efficient treatments for metastatic melanoma, in the fields of chemo, immuno or radiotherapy, and combined therapies (as biochemotherapy for example). At this time, no real benefit in term of global survival has been demonstrated.
It should be explained that radiopharmaceutical products comprise two functional components, one being radioactive and the other not being radioactive. The radioactive component makes possible the detection of the product in the context of the diagnosis and it constitutes the active agent in the case of therapeutic use. It is a radionuclide with appropriate physical properties. The nonradioactive component, for its part, is a molecule or tracer, optionally biological, intended to accumulate in the target organ, in the context of the present invention, in the melanoma, and to ensure the absorption of radioactivity by the latter. This nonradioactive component is determining for the biological behaviour of the radiopharmaceutical product in the body, in particular regarding the specificity and the pharmacokinetic profile.
Document EP 458 886 describes compounds of use in the diagnosis and treatment of malignant melanoma. From these molecules, N-(2-diethylaminoethyl)-4-iodobenzamide (BZA) forms in particular the subject of more detailed studies, and also N-(2-diethylaminoethyl)-2-iodobenzamide (BZA2), in the medical imaging application and more particularly for the scintigraphic detection of primary ocular melanoma and metastases of cutaneous and ocular melanomas. BZA2, radiolabelled with iodine-123, is object of a clinical trial for melanoma metastases imaging by SPECT.
The document U.S. Pat. No. 5,911,970 for its part describes, inter alia, other benzamide-derived compounds exhibiting a high specificity and affinity to cell surface sigma receptors of cancer cells.
Document WO 2005/089815 describes some radiohalogenated benzamide derivatives and their potential use for tumour diagnosis and tumour therapy of melanoma.
There thus exists, on one hand, a need to have available a specific tracer which makes it possible, from the time of the diagnosis, to carry out an assessment of extension of the disease and then, subsequently, monitoring and dosimetry studies. Such a tracer should advantageously make it possible the differential diagnosis of ocular melanoma, primary lesion, which is often difficult to identify.
On the other hand, as exposed above, treatments remain defeated with regard to disseminated melanoma and the development of novel specific therapeutic approaches for the treatment of melanoma is essential.
There is moreover a need to find new molecules, which depending on the radioisotope which is introduced thereon, are able to form a radiotracer usable for the diagnosis using PET or SPECT imaging and able to form an agent for the internal radionuclide therapy.
There is lastly a need for multimodal radiotracers widening the scope of imaging techniques in the field of diagnosis of melanoma, and more particularly a need of new tracers finding potential application in fluorine-18 PET imaging.
Today, fluorine-18, beyond its adequate physical and nuclear characteristics, appears as the most attractive positron-emitting radioisotope for radiopharmaceutical chemistry and PET imaging, part of this continuous growing interest probably due to the successful use in clinical oncology of [18F]FDG, the most widely used PET-radiopharmaceutical. Briefly, fluorine-18 displays simple decay and emission properties with a high 97% positron abundance. Compared with the other conventional short-lived positron-emitting radionuclides carbon-11, nitrogen-13 and oxygen-15, fluorine-18 has a relatively low positron energy (maximum 635 keV) and the shortest positron linear range in tissue (2.3 mm), resulting in the highest resolution in PET imaging. Its half-life (109.8 min) is long enough to give access to relatively extended imaging protocols compared to what is possible with carbon-11, therefore facilitating kinetic studies and high-quality plasma metabolite analysis. Moreover, from a chemical point of view, fluorine-18 allows multi-step synthetic approaches that can be extended over hours. Finally, fluorine-18 can be reliably and routinely produced at the multi-Curie level, using the well-characterized (p, n) nuclear reaction on an oxygen-18-enriched water target on widely implemented biomedical cyclotrons of a relatively low-energy proton beam (e.g., 18 MeV).
To conclude, the use of a specific tracer, radiolabelled by fluorine-18, in PET imaging could lead to an increase of sensitivity of this technique, compared with [18F]FDG, especially for the diagnosis of stage I (ocular) or II melanoma and the differential diagnosis with other tumours. Use of PET imaging is complementary to SPECT imaging and even in some contexts PET imaging, and more particularly fluorine-18 PET imaging, compared to SPECT allows better performances in terms of image quality or quantification of uptake namely for dosimetry.